Amino-tetralin derivatives as muscarinic receptor antagonists

ABSTRACT

This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I:  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are as defined in the specification, or individual isomers, racemic or non-racemic mixtures of isomers, or acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use and preparation as therapeutic drugs.

CROSS-REFERENCE

[0001] This application claims the benefit of priority of U.S.Provisional Patent Application Serial No. 60/336,675, filed Dec. 3,2001, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to amino-tetralin derivatives, associatedacceptable salts, or hydrates thereof, and associated compositions andmethods for use as M2/M3 selective muscarinic receptor antagonists.

BACKGROUND OF THE INVENTION

[0003] Acetylcholine (Ach) is the principal transmitter of theparasympathetic nervous system. The physiological actions of Ach aremediated by activation of either nicotinic or muscarinic receptors. Bothof these receptor classes are heterogeneous: e.g., the muscarinicreceptor family comprises five subtypes (M₁, M₂, M₃, M₄, and M₅) eachencoded by distinct genes and possessing unique pharmacology anddistribution.

[0004] Almost all smooth muscle tissues express both muscarinic M2 andM3 receptors, both of which have a functional role. M2 receptorsoutnumber M3 receptors by a proportion of approximately 4 to 1.Generally, M3 receptors mediate the direct contractile effects ofacetylcholine in the vast majority of smooth muscle tissues. M2receptors, on the other hand, cause smooth muscle contraction indirectlyby inhibiting sympathetically (β-adrenoreceptor)-mediated relaxation.

[0005] Compounds that act as antagonists of muscarinic receptors havebeen used to treat several disease states associated with impropersmooth muscle function, as well as in the treatment of cognitive andneurodegenerative disorders such as Alzheimer's disease. Until recently,most of these compounds have been non-selective for the variousmuscarinic receptor subtypes, leading to unpleasant anti-cholinergicside-effects such as dry mouth, constipation, blurred vision, ortachycardia. The most common of these side-effects is dry-mouthresulting from muscarinic receptor blockade in the salivary gland.Recently developed M2 or M3 specific antagonists have been shown to havereduced side effects. Evidence suggests that mechanistically, concurrentblockade of M2 and M3 receptors could be therapeutically effective inthe treatment of disease states associated with smooth muscle disorders.

[0006] Additionally, muscarinic receptor antagonists are front-linetherapy as bronchodilators in chronic obstructive pulmonary disease(COPD). It is thought that the efficacy of this class of molecules ismediated through antagonism of the natural transmitter (acetylcholine)at M3 receptors on airway smooth muscle and there may be additionalbenefit in COPD through inhibition of mucus secretion which may also bemediated through M3 receptors. The current standard antimuscarinic forthe treatment of COPD is ipratropium (Atrovent) which is administered byaerosol 4 times per day. More recently tiotropium (Spiriva) has beendeveloped by Boehringer-Ingelheim as a second-generation muscarinicantagonist and is expected to be launched in 2002 (in collaboration withPfizer). Tiotropium is also given by aerosol but has a slow off-ratefrom the M3 receptor and, as a result, causes a prolongedbronchodilatation. Tiotropium will be given once per day. Althoughtiotropium has high affinity for all muscarinic receptor subtypes, it isa quaternary ammonium compound which is poorly absorbed.

[0007] Few M2/M3 selective antagonists have been developed. The presentinvention fills this need by providing these types of antagonists usefulin the treatment of disease states associated with improper smoothmuscle function and respiratory disorders.

SUMMARY OF THE INVENTION

[0008] This invention relates to compounds comprising Formula I:

[0009] wherein:

[0010] R¹ is (C₁₋₆)alkyl;

[0011] R² is halogen or —OR′;

[0012] R³ is hydrogen or —OR′;

[0013] R′ is hydrogen, (C₁₋₆)alkyl, or SO₂R″;

[0014] R″ is (C₁₋₆)alkyl, haloalkyl, aryl or heteroaryl, wherein saidaryl or heteroaryl groups are optionally substituted with a groupselected from (C₁₋₆)alkyl, halo, haloalkyl, cyano, nitro, alkylsulfonyl,and alkylsulfonylamino,

[0015] R⁴ is (C₁₋₆)alkyl,

[0016] aryl, heterocyclyl, or heteroaryl, wherein said aryl,heterocyclyl or heteroaryl groups are optionally substituted with agroup selected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano,amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl,urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl,

[0017] or —NR⁵R⁶; and

[0018] R⁵ and R⁶ are independently of each other hydrogen, (C₁₋₆)alkyl,aryl or heterocyclyl; wherein said aryl or heterocyclyl groups areoptionally substituted with (C₁₋₆)alkyl, halo, haloalkyl, cyano,(C₁₋₆)alkoxy, and alkylsulfonyl,

[0019] or prodrugs, individual isomers, racemic or non-racemic mixturesof isomers, or salts or solvates thereof.

[0020] In preferred embodiments R² is (C₁₋₆)alkoxy, hydroxy or —OSO₂R″wherein R″ is (C₁₋₆)alkyl, haloalkyl, aryl or heteroaryl, and R³ ishydrogen or (C₁₋₆)alkyl; in another preferred embodiment R² is(C₁₋₆)alkoxy and R³ is hydrogen, and in another preferred embodiment R²and R³ are (C₁₋₆)alkoxy.

[0021] In another preferred embodiment R⁴ is (C₁₋₆)alkyl, and withinthis embodiment other preferred group of compounds is that wherein R¹ isethyl or propyl.

[0022] In another preferred embodiment R⁴ is an aryl group; and inanother preferred embodiment R⁴ is phenyl optionally substituted with agroup selected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano,amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl,urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl, and within this embodimentother preferred group of compounds is that wherein R¹ is ethyl orpropyl. Another preferred group of compounds is that wherein R² is —OR′,and R³ is —OR′ or hydrogen.

[0023] In another preferred embodiment R⁴ is a heteroaryl group; and inanother preferred embodiment R⁴ is selected from furanyl, thiophenyl,isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionallysubstituted with one or two (C₁-₆) alkyl, and within this embodimentanother preferred group of compounds is that wherein R¹ is ethyl orpropyl, and another preferred group of compounds is that wherein R² is—OR′, and R³ is —OR′ or hydrogen.

[0024] In another preferred embodiment R⁴ is a heterocyclyl group; andin another preferred embodiment R⁴ is piperidinyl, pyrrolidinyl,morpholinyl, piperazinyl, diazepanyl, all optionally substituted withone or two (C₁₋₆)alkyl or alkylcarbonyl groups, and within thisembodiment another preferred group of compounds is that wherein R¹ isethyl or propyl, and another preferred group of compounds is thatwherein R² is —OR′, and R³ is —OR′ or hydrogen.

[0025] In another preferred embodiment R⁴ is —NR⁵R⁶, and R⁵ is(C₁₋₆)alkyl and R⁶ is hydrogen or (C₁₋₆)alkyl; and in another preferredembodiment R⁴ is —NR⁵R⁶, R⁵ is heterocyclyl and R⁶ is hydrogen, andwithin this embodiment another preferred group of compounds is thatwherein R¹ is ethyl or propyl, and another preferred group of compoundsis that wherein R² is —OR′, and R³ is —OR′ or hydrogen.

[0026] In another aspect, the invention relates to pharmaceuticalcompositions containing a therapeutically effective amount of at leastone compound of Formula I, or individual isomers, racemic or non-racemicmixtures of isomers and salts or solvates thereof, in admixture with atleast one suitable carrier.

[0027] In another aspect, this invention relates to a method oftreatment of a disease in a mammal treatable by administration of atleast one compound of Formula I, having selective activity for the M2and M3 muscarinic receptors, in particular a method of treatment in asubject having a disease state comprising smooth muscle disorders;preferably genitourinary tract disorders, respiratory tract disorders,gastrointestinal tract disorders; more preferably genitourinary tractdisorders such as overactive bladder or detrusor hyperactivity and itssymptoms, such as the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity and the like; and the symptoms usually manifestedin detrusor hyperreflexia (neurogenic bladder), in conditions such asoutlet obstruction, outlet insufficiency, pelvic hypersensitivity, or inidiopathic conditions such as detrusor instability, and the like. Inanother preferred embodiment, the disease comprises respiratory tractdisorders such as allergies and asthma. In another preferred embodiment,the disease state comprises gastrointestinal disorders.

[0028] In another aspect, the invention relates to a process forpreparing a compound of Formula I, which process comprises reacting acompound having a general formula d:

[0029] wherein R¹, R², and R³ are as described in the summary of theinvention, with a compound of formula R⁴C(O)L, wherein L is a leavinggroup and R⁴ is as described in the summary of the invention, to give acompound of Formula I:

[0030] wherein R¹, R², R³ and R⁴ are as described in the summary of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Definitions

[0032] Unless otherwise stated, the following terms used in thisApplication, including the specification and claims, have thedefinitions given below. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an”, and“the” include plural referents unless the context clearly dictatesotherwise.

[0033] “Alkyl” means the monovalent linear or branched saturatedhydrocarbon radical, having from one to six carbon atoms inclusive,unless otherwise indicated. Examples of alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl,sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.

[0034] “Aryl” means the monovalent aromatic carbocyclic radicalconsisting of one individual ring, or one or more fused rings in whichat least one ring is aromatic in nature, which can optionally besubstituted with one or more, preferably one or two, substituentsselected from hydroxy, cyano, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, haloalkoxy,alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, cyano, alkoxycarbonyl,amino, alkylamino, alkylsulfonyl, alkylcarbonyl, arylsulfonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, alkylaminocarbonyl, arylcarbonylamino, heterocyclyl,heteroaryl, and urea, unless otherwise indicated. Alternatively twoadjacent atoms of the aryl ring may be substituted with a methylenedioxyor ethylenedioxy group. Examples of aryl radicals include, but are notlimited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl,tert-butyl-phenyl, 1,3-benzodioxolyl, o-tolyl, trifluoromethylphenyl,methanesulfonylphenyl, ureaphenyl, pyrrolydinylphenyl, tetrazolylphenyl,and the like.

[0035] “Heteroaryl” means the monovalent aromatic cyclic radical havingone or more rings, preferably one to three rings, of four to eight atomsper ring, incorporating one or more heteroatoms, preferably one or two,within the ring (chosen from nitrogen, oxygen, or sulfur), which canoptionally be substituted with one or more, preferably one or twosubstituents selected from hydroxy, cyano, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,cyano, alkoxycarbonyl, amino, alkylamino, alkylcarbonyl, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and urea, unless otherwiseindicated. Examples of heteroaryl radicals include, but are not limitedto, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazinyl, pyrazolyl,tetrazolyl, thienyl, furanyl, pyridinyl, quinolinyl, isoquinolinyl,benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl,isoindolyl, quinolinyl, isoquinolinyl, naphthyridinyl,benezenesulfonyl-thiophenyl, and the like.

[0036] “Heterocyclyl” means the monovalent saturated cyclic radical,consisting of one or more rings, preferably one to two rings, of threeto eight atoms per ring, incorporating one or more ring heteroatoms(chosen from N, O or S(O)₀₋₂), and which can optionally be substitutedwith one or more, preferably one or two substituents selected fromhydroxy, oxo, cyano, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, haloalkoxy, alkylthio,halo, haloalkyl, hydroxyalkyl, nitro, cyano, alkoxycarbonyl, amino,alkylamino, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and urea unless otherwiseindicated. Examples of heterocyclic radicals include, but are notlimited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, thiomorpholinyl, 2-oxo-pyrrolidinyl,3,5-dimethyl-piperazinyl, 4-methylpiperazin-1-yl,1-methyl-piperidin-4-yl and the like.

[0037] “Haloalkyl” means the alkyl radical as defined herein substitutedin any position with one or more halogen atoms as defined herein.Examples of haloalkyl radicals include, but are not limited to,1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0038] “Halogen” means the radical fluoro, bromo, chloro, and/or iodo.

[0039] “Optional” or “optionally” means that the subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present, and that the description includes single,double, or triple bonds.

[0040] “Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkane- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

[0041] “Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyincludes groups protected as acetates, haloalkyl carbonates, benzylethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, preferablytert-butyl, benzyl or methyl esters. Examples of protecting groups canbe found in T. W. Greene et al., Protective Groups in Organic Chemistry,(J. Wiley, 2^(nd) ed. 1991) and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (J. Wiley and Sons 1971-1996).

[0042] “Amino-protecting group” means the protecting group that refersto those organic groups intended to protect the nitrogen atom againstundesirable reactions during synthetic procedures and includes, but isnot limited to, benzyl (Bnz), benzyloxycarbonyl (carbobenzyloxy, Cbz),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like. It ispreferred to use either Boc or Cbz as the amino-protecting group becauseof the relative ease of removal, for example by mild acids in the caseof Boc, e.g., trifluoroacetic acid or hydrochloric acid in ethylacetate; or by catalytic hydrogenation in the case of Cbz.

[0043] “Deprotection” or “deprotecting” means the process by which aprotective group is removed after the selective reaction is completed.Certain protective groups may be preferred over others due to theirconvenience or relative ease of removal. Deprotecting reagents forprotected hydroxyl or carboxyl groups include potassium or sodiumcarbonates, lithium hydroxide in alcoholic solutions, zinc in methanol,acetic acid, trifluoroacetic acid, palladium catalysts, or borontribromide, and the like.

[0044] “Isomerism” means compounds that have identical molecularformulae but that differ in the nature or the sequence of bonding oftheir atoms or in the arrangement of their atoms in space. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. Stereoisomers that are not mirror images of one anotherare termed “diastereoisomers”, and stereoisomers that arenon-superimposable mirror images are termed “enantiomers”, or sometimesoptical isomers. A carbon atom bonded to four nonidentical substituentsis termed a “chiral center”.

[0045] “Chiral isomer” means a compound with one chiral center. It hastwo enantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n−1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al. 1966, Angew. Chem. Inter. Edit., 5, 385; errata 511; Cahnet al. 1966, Angew. Chem., 78, 413; Cahn and Ingold 1951, J. Chem. Soc.(London), 612; Cahn et al. 1956, Experentia, 12, 81; Cahn, J. 1964,Chem.Educ., 41, 116).

[0046] “Geometric Isomers” means the diastereomers that owe theirexistence to hindered rotation about double bonds. These configurationsare differentiated in their names by the prefixes cis and trans, or Zand E, which indicate that the groups are on the same or opposite sideof the double bond in the molecule according to the Cahn-Ingold-Prelogrules.

[0047] “Atropic isomers” means the isomers owing their existence torestricted rotation caused by hindrance of rotation of large groupsabout a central bond.

[0048] “Substantially pure” means at least about 80 mole percent, morepreferably at least about 90 mole percent, and most preferably at leastabout 95 mole percent of the desired enantiomer or stereoisomer ispresent.

[0049] “Pharmaceutically acceptable” means that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary as well as humanpharmaceutical use.

[0050] “Acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

[0051] (1) acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid,citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid, and the like; or

[0052] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic or inorganic base. Acceptable organic bases includediethanolamine, ethanolamine, N-methylglucamine, triethanolamine,tromethamine, and the like. Acceptable inorganic bases include aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate andsodium hydroxide.

[0053] The preferred acceptable salts are the salts formed fromhydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid, andphosphoric acid.

[0054] It should be understood that all references to acceptable saltsinclude solvent addition forms (solvates) or crystal forms (polymorphs)as defined herein, of the same acid addition salt.

[0055] “Crystal forms” (or polymorphs) means crystal structures in whicha compound can crystallize in different crystal packing arrangements,all of which have the same elemental composition. Different crystalforms usually have different X-ray diffraction patterns, infraredspectra, melting points, density hardness, crystal shape, optical andelectrical properties, stability and solubility. Recrystallizationsolvent, rate of crystallization, storage temperature, and other factorsmay cause one crystal form to dominate.

[0056] “Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

[0057] “Prodrug” or “pro-drug” means a pharmacologically inactive formof a compound which must be metabolized in vivo, e.g., by biologicalfluids or enzymes, by a subject after administration into apharmacologically active form of the compound in order to produce thedesired pharmacological effect. Prodrugs of a compound of Formula I areprepared by modifying one or more functional group(s) present in thecompound of Formula I in such a way that the modification(s) may becleaved in vivo to release the parent compound. Prodrugs includecompounds of Formula I wherein a hydroxy, amino, sulfhydryl, carboxy orcarbonyl group in a compound of Formula I is bonded to any group thatmay be cleaved in vivo to regenerate the free hydroxyl, amino,sulfhydryl, carboxy or carbonyl group respectively. Examples of prodrugsinclude, but are not limited to, esters (e.g. acetate,dialkylaminoacetates, formates, phosphates, sulfates and benzoatederivatives) and carbamates of hydroxy functional groups (e.g.N,N-dimethylcarbonyl), esters of carboxyl functional groups (e.g. ethylesters, morpholinoethanol esters), N-acyl derivatives (e.g. N-acetyl),N-Mannich bases, Schiff bases and enaminones of amino functional groups,oximes, acetals, ketals, and enol esters of ketones and aldehydefunctional groups in compounds of Formula I, and the like.

[0058] The prodrug can be metabolized before absorption, duringabsorption, after absorption, or at a specific site. Although metabolismoccurs for many compounds primarily in the liver, almost all othertissues and organs, especially the lung, are able to carry out varyingdegrees of metabolism. Prodrug forms of compounds may be utilized, forexample, to improve bioavailability, improve subject acceptability suchas by masking or reducing unpleasant characteristics such as bittertaste or gastrointestinal irritability, alter solubility such as forintravenous use, provide for prolonged or sustained release or delivery,improve ease of formulation, or provide site-specific delivery of thecompound. Reference to a compound herein includes prodrug forms of acompound. Prodrugs are described in The Organic Chemistry of Drug Designand Drug Action, by Richard B. Silverman, Academic Press, San Diego,1992. Chapter 8: “Prodrugs and Drug delivery Systems” pp.352-401; Designof Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

[0059] “Subject” means mammals and non-mammals. Mammals means any memberof the Mammalia class including, but not limited to, humans, non-humanprimates such as chimpanzees and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, and swine; domesticanimals such as rabbits, dogs, and cats; laboratory animals includingrodents, such as rats, mice, and guinea pigs; and the like. Examples ofnon-mammals include, but are not limited to, birds, and the like.

[0060] “Therapeutically effective amount” means an amount of a compoundthat, when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compoundand disease state being treated, the severity of the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

[0061] “Pharmacological effect” as used herein encompasses effectsproduced in the subject that achieve the intended purpose of a therapy.In one preferred embodiment, a pharmacological effect means that primaryindications of the subject being treated are prevented, alleviated, orreduced. For example, a pharmacological effect would be one that resultsin the prevention, alleviation or reduction of primary indications in atreated subject. In another preferred embodiment, a pharmacologicaleffect means that disorders or symptoms of the primary indications ofthe subject being treated are prevented, alleviated, or reduced. Forexample, a pharmacological effect would be one that results in theprevention or reduction of primary indications in a treated subject.

[0062] “Disease state” means any disease, condition, symptom, orindication.

[0063] “Treating” or “treatment” of a disease state includes:

[0064] (1) preventing the disease state, i.e. causing the clinicalsymptoms of the disease state not to develop in a subject that may beexposed to or predisposed to the disease state, but does not yetexperience or display symptoms of the disease state;

[0065] (2) inhibiting the disease state, i.e., arresting the developmentof the disease state or its clinical symptoms; or

[0066] (3) relieving the disease state, i.e., causing temporary orpermanent regression of the disease state or its clinical symptoms.

[0067] “Antagonist” means a molecule such as a compound, a drug, anenzyme inhibitor, or a hormone, that diminishes or prevents the actionof another molecule or receptor site.

[0068] “Disorders of the urinary tract” or “uropathy” usedinterchangeably with “symptoms of the urinary tract” means thepathologic changes in the urinary tract. Symptoms of the urinary tractinclude overactive bladder (also known as detrusor hyperactivity),outlet obstruction, outlet insufficiency, and pelvic hypersensitivity.

[0069] “Overactive bladder” or “Detrusor hyperactivity” includes, but isnot limited to, the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

[0070] “Outlet obstruction” includes, but is not limited to, benignprostatic hypertrophy (BPH), urethral stricture disease, tumors and thelike. It is usually symptomatically manifested as obstructive (low flowrates, difficulty in initiating urination, and the like) or irritative(urgency, suprapubic pain, and the like).

[0071] “Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, or mixed incontinence.It is usually symptomatically manifested as stress incontinence.

[0072] “Pelvic Hypersensitivity” includes but is not limited to, pelvicpain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia,urethritis, orchidalgia, and the like. It is symptomatically manifestedas pain, inflammation or discomfort referred to the pelvic region, andusually includes symptoms of overactive bladder.

[0073] Throughout the application the following abbreviations are usedwith the following meanings: Bnz benzyl Boc ter-butoxycarbonyl BPHBenign prostatic hypertrophy or benign prostatic hyperplasia DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide EDCI1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc Ethylacetate Hal Halogen or halide HOBT 1-Hydroxybenzotriazole hydrate ProProtective group TFA Trifluoroacetic acid TFAA Trifluoroacetic acidanhydride THF Tetrahydrofuran

[0074] Nomenclature

[0075] The naming and numbering of the compounds of this invention isillustrated below:

[0076] In general, the nomenclature used in this Application is based onAUTONOM™, a Beilstein Institute computerized system for the generationof IUPAC systematic nomenclature.

[0077] For example a compound of Formula I wherein R¹ is propyl, R² andR³ are —OCH₃, and R⁴ is 4-methyl-piperazin-1-yl is named:{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone.

[0078] Preferred Compounds

[0079] Among compounds of the present invention set forth in the Summaryof the Invention, certain compounds of Formula I, or prodrugs,individual isomers, racemic or non-racemic mixtures of isomers, oracceptable salts or solvates thereof, are preferred:

[0080] R¹ is preferably (C₁₋₆)alkyl, more preferably ethyl and propyl;

[0081] R² is preferably halogen or —OR′, more preferably halogen or(C₁₋₆)alkoxy;

[0082] R³ is preferably hydrogen or —OR′, more preferably hydrogen or(C₁₋₆)alkoxy;

[0083] R′ is preferably hydrogen, (C₁₋₆)alkyl, or —SO₂R″, morepreferably (C₁₋₆)alkyl,

[0084] R″ is preferably (C₁₋₆)alkyl, haloalkyl, aryl or heteroaryl, morepreferably aryl or heteroaryl;

[0085] R⁴ is —NR⁵R⁶, aryl, heterocyclyl or heteroaryl, more preferablyheterocyclyl or heteroaryl;

[0086] R⁵ and R⁶ are independently of each other hydrogen, (C₁₋₆)alkyl,aryl, or heterocylyl, more preferably (C₁₋₆)alkyl or heterocyclyl.

[0087] Other preferred compounds of the present invention include theacceptable salts of the compounds of the present invention, wherein theacceptable salts are preferably formed from hydrochloric acid or2,2,2-trifluoroacetic acid.

[0088] Exemplary particularly preferred compounds, or prodrugs,individual isomers, racemic or non-racemic mixtures of isomers, or saltsor solvates thereof include:

[0089]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;

[0090]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone;

[0091]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;

[0092]{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;

[0093]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone;

[0094]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;

[0095]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone,and

[0096]{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone.

General Synthetic Reaction Schemes

[0097] Compounds of the present invention may be made by the methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

[0098] The starting materials and reagents used in preparing thesecompounds generally are either available from commercial suppliers, suchas Aldrich Chemical Co., or are prepared by methods known to thoseskilled in the art following procedures set forth in references such asFieser and Fieser 1991 Reagents for Organic Synthesis; Wiley & Sons: NewYork, Volumes 1-15; Rodd 1989 Chemistry of Carbon Compounds, ElsevierScience Publishers, Volumes 1-5 and Supplementals; and 1991 OrganicReactions, Wiley & Sons: New York, Volumes 1-40. The following syntheticreaction schemes are merely illustrative of some methods by which thecompounds of the present invention may be synthesized, and variousmodifications to these synthetic reaction schemes may be made and willbe suggested to one skilled in the art having referred to the disclosurecontained in this Application.

[0099] The starting materials and the intermediates of the syntheticreaction schemes may be isolated and purified if desired usingconventional techniques, including but not limited to filtration,distillation, crystallization, chromatography, and the like. Suchmaterials may be characterized using conventional means, includingphysical constants and spectral data.

[0100] Unless specified to the contrary, the reactions described hereinpreferably take place at atmospheric pressure over a temperature rangefrom about −78° C. to about 150° C., more preferably from about 0° C. toabout 125° C., and most preferably and conveniently at about room (orambient) temperature, e.g., about 20° C.

[0101] A compound of Formula b, wherein Pro is a protective group, cangenerally be prepared by coupling a tetralone of Formula a with aprotected amino piperidine under reductive amination conditions.Suitable reducing conditions include sodium triacetoxyborohydride,sodium cyanoborohydride, titanium isopropoxide and sodiumcyanoborohydride, hydrogen and a metal catalyst and hydrogentransferring agents such as cyclohexene, formic acid and its salts, zincand hydrochloric acid formic acid or borane sulfide followed bytreatment with formic acid. Suitable organic solvents for the reactioninclude dichloromethane, 1,2-dichloroethane, tetrahydrofuran, alcoholsor ethyl acetate, and the like. Preferably the reaction is carried outunder basic conditions with sodium triacetoxyborohydride in1,2-dichloroethane. Reductive amination procedures are described in thechemical literature. For example, J. Org. Chem., 1996, 61, 3849 andTetrahedron Letters, 1996, 37, 3977, describe methods utilizing sodiumtriacetoxyborohydride as a reagent for the reductive amination ofaldehydes with a wide variety of amines. Compound b is further coupledunder reductive amination conditions as described herein, with acarboxaldehyde to generally give a compound of Formula c, wherein R¹ isas described in the summary of the invention, which after deprotectionof the piperidine group under conditions well known in the art asdescribed herein, to give a compound of Formula d, can undergoacylation, with an acid chloride of formula R⁴C(O)L, wherein L is aleaving group and R⁴ is as described in the summary of the invention,under conditions well known in the art, to generally give a compound ofFormula I.

[0102] The conventional starting materials of Scheme A are commerciallyavailable or are known to, or can readily be synthesized by those ofordinary skill in the art.

General Utility

[0103] Compounds that act as antagonists of muscarinic receptors havebeen used to treat several disease states associated with impropersmooth muscle function as well as in the treatment of cognitive andneurodegenerative disorders such as Alzheimer's disease. Until recently,most of these compounds have been non-selective for the variousmuscarinic receptor subtypes, leading to unpleasant anti-cholinergicside-effects such as dry mouth, constipation, blurred vision ortachycardia, the most common of which is dry-mouth that results frommuscarinic receptor blockade in the salivary gland. Recently developedM2 or M3 specific antagonists have been shown to have reduced sideeffects. Evidence suggests that mechanistically, concurrent blockade ofM2 and M3 receptors could be therapeutically effective in the treatmentof disease states associated with smooth muscle disorders, such asgenitourinary tract disorders, respiratory tract disorders,gastrointestinal tract disorders, and smooth muscle disorders.

[0104] Genitourinary tract disorders treatable with compounds of thisinvention specifically include overactive bladder or detrusorhyperactivity and its symptoms such as the changes symptomaticallymanifested as urgency, frequency, reduced bladder capacity, incontinenceepisodes, and the like; the changes urodynamically manifested as changesin bladder capacity, micturition threshold, unstable bladdercontractions, sphincteric spasticity, and the like; and the symptomsusually manifested in detrusor hyperreflexia (neurogenic bladder), inconditions such as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

[0105] Gastrointestinal tract disorders treatable with compounds of thisinvention specifically include irritable bowel syndrome, diverticulardisease, achalasia, gastrointestinal hypermotility disorders, anddiarrhea. Respiratory tract disorders treatable with compounds of thisinvention specifically include chronic obstructive pulmonary disease,including chronic bronchitis, emphysema, asthma and pulmonary fibrosis.

[0106] Compounds with selectivity for the M2 muscarinic receptor havealso been shown to be useful in the treatment of cognitive andneurodegenerative diseases such as for example, Alzheimer's disease, asdescribed in J. Med. Chem. 1993, 36, 3734-3737. U.S. Pat. No. 6,294,554describes muscarinic antagonists for the treatment of cognitivedisorders.

[0107] These and other therapeutic uses are described, for example, inGoodman & Gilman, 1996 The Pharmacological Basis of Therapeutics, ninthedition, McGraw-Hill, New York, Chapter 26:601-616; and Coleman, R. A.,1994, Pharmacological Reviews, 46:205-229.

Testing

[0108] The compounds of this invention are muscarinic receptorantagonists. The muscarinic receptor affinity of test compounds can bedetermined by an in vitro receptor binding assay which utilizes a cellmembrane preparation from the Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (M₁-M₅), and is described in moredetail in Example 12.

[0109] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated saliva secretion in anesthetizedrats, and is described in more detail in theOxotremorine/Pilocarpine-induced salivation (OIS/PIS) model inanesthetized rats, Example 13.

[0110] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction in anesthetizedrats, and is described in more detail in the inhibition ofvolume-induced contractions assay, Example 14.

[0111] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction and salivasecretion in anesthetized dogs, and is described in more detail inExample 15.

[0112] The muscarinic antagonist properties of the test compounds asanti-bronchoconstriction agents can be identified by an in vivo assay inanesthetized rats as described in more detail in Example 16.

Administration and Pharmaceutical Composition

[0113] The present invention includes pharmaceutical compositionscomprising at least one compound of the present invention, or a prodrug,an individual isomer, a racemic or non-racemic mixture of isomers or anacceptable salt, or solvate thereof together with at least oneacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

[0114] In general, the compounds of the present invention will beadministered in a therapeutically effective amount by any of theaccepted modes of administration for agents that serve similarutilities. Suitable dosage ranges are typically 1-500 mg daily,preferably 1-100 mg daily, and most preferably 1-30 mg daily, dependingupon numerous factors such as the severity of the disease to be treated,the age and relative health of the subject, the potency of the compoundused, the route and form of administration, the indication towards whichthe administration is directed, and the preferences and experience ofthe medical practitioner involved. One of ordinary skill in the art oftreating such diseases will be able, without undue experimentation andin reliance upon personal knowledge and the disclosure of thisApplication, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease. In general,compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

[0115] A compound or compounds of the present invention, together withone or more conventional adjuvants, carriers, or diluents, may be placedinto the form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about ten (10) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

[0116] The compounds of the present invention may be formulated in awide variety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavoring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

[0117] Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0118] The compounds of the present invention may be formulated forparenteral administration (e.g., by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, for example solutions in aqueous polyethylene glycol. Examplesof oily or nonaqueous carriers, diluents, solvents or vehicles includepropylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil),and injectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0119] The compounds of the present invention may be formulated fortopical administration to the epidermis as ointments, creams or lotions,or as a transdermal patch. Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Lotions may be formulated with anaqueous or oily base and will in general also containing one or moreemulsifying agents, stabilizing agents, dispersing agents, suspendingagents, thickening agents, or coloring agents. Formulations suitable fortopical administration in the mouth include lozenges comprising activeagents in a flavored base, usually sucrose and acacia or tragacanth;pastilles comprising the active ingredient in an inert base such asgelatin and glycerin or sucrose and acacia; and mouthwashes comprisingthe active ingredient in a suitable liquid carrier.

[0120] The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

[0121] The compounds of the present invention may be formulated fornasal administration. The solutions or suspensions are applied directlyto the nasal cavity by conventional means, for example, with a dropper,pipette or spray. The formulations may be provided in a single ormultidose form. In the latter case of a dropper or pipette, this may beachieved by the patient administering an appropriate, predeterminedvolume of the solution or suspension. In the case of a spray, this maybe achieved for example by means of a metering atomizing spray pump.

[0122] The compounds of the present invention may be formulated foraerosol administration, particularly to the respiratory tract andincluding intranasal administration. The compound will generally have asmall particle size for example of the order of five (5) microns orless. Such a particle size may be obtained by means known in the art,for example by micronization. The active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

[0123] The compounds of the present invention can be formulated intransdermal or subcutaneous drug delivery devices. These deliverysystems are advantageous when sustained release of the compound isnecessary and when patient compliance with a treatment regimen iscrucial. Compounds in a transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

[0124] The pharmaceutical preparations are preferably in unit dosageforms. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

[0125] Other suitable pharmaceutical carriers and their formulations aredescribed in Remington, 1995, The Science and Practice of Pharmacy,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Examples 5-11.

EXAMPLES

[0126] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

[0127]

[0128] Step 1:

[0129](1-Benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine

[0130] To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (10 g,56.7 mmol) and 1-benzyl-piperidin-4-ylamine (12.7 mL, 62.4 mmol) indichloroethane (50 mL) under a nitrogen atmosphere was added sodiumtriacetoxyborohydride (30 g, 141.8 mmol, 3.5 eq.) in a single portion.The reaction was stirred at room temperature for 24 h. The reaction wasconcentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq.KOH (50 mL). The aqueous layer was extracted twice more with EtOAc (2×50mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated to afford a dark oil. This materialwas used directly in Step 2.

[0131] Step 2:

[0132](1-Benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine

[0133] To a solution of(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-aminefrom Step 1 and propionaldehyde (4.5 mL, 62.4 mmol) in dichloroethane(200 mL) under a nitrogen atmosphere was added sodiumtriacetoxyborohydride (24 g, 0.113 mol, 2 eq.) in a single portion. Thereaction was stirred at room temperature for 24 h then concentrated invacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH(50 mL). The aqueous phase was extracted twice more with EtOAc (2×30mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated onto silica (10 g). This was placed on top of a flashcolumn and eluted with 20% hexanes in acetone. The fractions containingproduct were pooled and concentrated to afford(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amineas a clear oil (6.86 g).

[0134] Step 3:

[0135](7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

[0136] A solution of(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine(6.86 g, 14.47 mmol) in absolute ethanol (100 mL) was poured onto aslurry of 20% Palladium hydroxide/C (1.4 g) in absolute ethanol (10 mL).The mixture was placed under a hydrogen atmosphere on the Parr shaker at50 psi for 20 h. The reaction mixture was filtered, and concentrated togive(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(4.2 g).

[0137] Step 4a:

[0138]{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

[0139] To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.025 M in dichloromethane, 50 μmole) was added 200 μL of0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. underN₂. Concentrated in vacuo. The final product was isolated by preparativeRPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1%TFA)) to afford{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone1 (11.9 mg), [M+H]⁺=461.

[0140] Step 4b:

[0141] Alternatively an Acid May Be Used in the Last Step as anAcylating Agent.

[0142]1-(4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone

[0143] To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.25 M in dimethyl formamide, 50 μmole) was added1-acetylpiperidine-4-carboxylic acid (220 μL of 0.25M in DMF), 300 μL ofEDCI (0.25M in DMF) and 220 uL of HOBT (0.25M in DMF) and 30 μL DIEA.The solution was allowed to stir for 48 h at 25° C. under N₂.Concentrated in vacuo. The final product was isolated by preparativeRPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1%TFA)) to afford1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone2 (5.2 mg), [M+H]⁺=456.

[0144] Similarly following the procedures described above in Example 1and using the appropriate acylating compounds in Step 4a or Step 4b, thefollowing compounds were prepared:

[0145]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-otolyl-methanone3, [M+H]⁺=421;

[0146]furan-2-yl-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone4, [M+H]⁺=397;

[0147]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid diethylamide 5, [M+H]⁺=397;

[0148](3,5-dimethyl-isoxazol-4-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone6, [M+H]⁺=426;

[0149](4-methanesulfonyl-phenyl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone7, [M+H]⁺=485;

[0150](4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-urea8, [M+H]⁺=465;

[0151]1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-pyrrolidin-2-one9, [M+H]⁺=465;

[0152]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-[4-(1H-tetrazol-5-yl)-phenyl]-methanone10, [M+H]⁺=475;

[0153]N-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-methanesulfonamide11, [M+H]⁺=500;

[0154]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid methylamide 12, [M+H]⁺=360;

[0155]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid (4-trifluoromethyl-phenyl)-amide 13, [M+H]⁺=490;

[0156]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid (3-cyano-phenyl)-amide 14, [M+H]⁺=447;

[0157]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone15, [M+H]⁺=381;

[0158]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone16, [M+H]⁺=451;

[0159]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid isopropylamide 17, [M+H]⁺=424;

[0160]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid dimethylamide 18, [M+H]⁺=410;

[0161]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone19, [M+H]⁺=450;

[0162]{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1H-pyrazol-4-yl)-methanone20, [M+H]⁺=433;

[0163]((3R,5S)-3,5-Dimethyl-piperazin-1-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone21, [M+H]⁺=479;

[0164]4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid piperidin-4-ylamide 22, [M+H]⁺=465;

[0165]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone23, [M+H]⁺=465;

[0166](1H-imidazol-4-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone24, [M+H]⁺=433;

[0167][1,4]diazepan-1-yl-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone25, [M+H]⁺=465;

[0168]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1-methyl-piperidin-4-yl)-methanone26, [M+H]⁺=395; and

[0169]{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-3-yl-methanone27, [M+H]⁺=450.

[0170] Similarly, following the procedure described above in Example 1,but replacing 7-methoxy-3,4-dihydro-1H-naphthalen-2-one with6,7-dimethoxy-3,4-dihydro-1H-naphthalen-2-one in Step 1 and using theappropriate acylating compounds in Step 4a or Step 4b, the followingcompounds were prepared:

[0171]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone28, [M+H]⁺=480;

[0172]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone29, [M+H]⁺=482;

[0173]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone30, [M+H]⁺=481;

[0174]4-[(6,7-Dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid diethylamide 31, [M+H]⁺=468;

[0175]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone32, [M+H]⁺=495; and

[0176]{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1-methyl-piperidin-4-yl)-methanone33, [M+H]⁺=494.

Example 2

[0177]{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone

[0178] Step 1:

[0179]4-(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

[0180] To a solution of 7-bromo-3,4-dihydro-1H-naphthalen-2-one (500 mg,2.2 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester(445 mg, 2.2 mmol) in dichloroethane (50 mL) under a nitrogen atmospherewas added sodium triacetoxyborohydride (1.29 g, 5.55 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h. Thereaction was concentrated in vacuo and partitioned between EtOAc (100mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice morewith EtOAc (2×50 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. Flashchromatography on silica gel eluting with 5% methanol/methylene chlorideafforded4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (610 mg).

[0181] Step 2:

[0182]4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicAcid Tert-Butyl Ester

[0183] To a solution of4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (610 mg, 1.5 mmol) and propionaldehyde (0.1 mL,1.5 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere wasadded sodium triacetoxyborohydride (795 mg, 3.75 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h thenconcentrated in vacuo. The residue was partitioned between EtOAc (75 mL)and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more withEtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated onto silica (10 g). This was placed on top ofa flash column and eluted with 20% hexanes in acetone. The fractionscontaining product were pooled and concentrated to afford4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (587 mg).

[0184] Step 3:

[0185](7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

[0186] To a solution of4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (347 g, 0.77 mmol) in methylene chloride (30 mL)under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). Thereaction was stirred at room temperature for 30 min., and concentratedin vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq.KOH (50 mL). The organic layer was separated, dried over MgSO₄,filtered, and concentrated to afford(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(203 mg).

[0187] Step 4:

[0188]{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone

[0189] To a solution of the(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of 0.25M solution of morpholine 4-carbonyl chloride in dichloromethane and 30μL of DIEA. The reaction was stirred at 25° C. for 24 h. Concentrated invacuo. The final product was isolated by preparative RPHPLC (YMCCombiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl)-pyrrolidin-1-yl-methanone34 (4.6 mg), [M+H]⁺=562.

[0190] Similarly following the procedure described above in Example 2but replacing in Step 4 morpholine-4-carbonyl chloride with theappropriate carbonyl chlorides, the following additional compounds wereprepared:

[0191]{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone35, [M+H]⁺=499;

[0192]{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone36, [M+H]⁺=606;

[0193]4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone37, [M+H]⁺=478; and

[0194]4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid dimethylamide 38, [M+H]⁺=543.

Example 3

[0195]{4-[((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-Piperidin-4-yl-methanone

[0196] Step 1:

[0197]4-((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

[0198] To a solution of(R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (6.0g, 28.1 mmol)(prepared as described in the French patent FR 2,653,765 oravailable commercially) and 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (6.7 g, 33.7 mmol, 1.2 eq.) in dichloroethane (200 mL)under an inert atmosphere was added sodium triacetoxyborohydride (14.9g, 70.2 mmol, 2.5 eq). The reaction was stirred at room temperature for24 h then concentrated in vacuo. The residue was partitioned betweenEtOAc (200 mL) and 5% KOH (150 mL). The aqueous layer was extractedtwice more with EtOAc (2×75 mL). The combined organic layers were dried(MgSO₄), filtered, and concentrated to afford4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester as a yellow oil (9.7 g).

[0199] Step 2:

[0200]((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

[0201] To a solution of4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (9.7 g, 23.4 mmol) and propionaldehyde (2.0 mL,28.1 mmol) in dichloroethane (150 mL) under a nitrogen atmosphere wasadded sodium triacetoxyborohydride (10.9 mg, 51.5 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h thenconcentrated in-vacuo. The residue was partitioned between EtOAc (175mL) and 5% aq. KOH (150 mL). The aqueous phase was extracted twice morewith EtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated to afford 10.0 g of the protected amine,which was treated with trifluoroacetic acid as described herein toafford((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(7.0 g).

[0202] Step 3:

[0203]{4-[((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone

[0204] Under an inert atmosphere was combined((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butylester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 g,23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane(140 mL). The mixture was stirred at room temperature for 48 h thenconcentrated in vacuo. The residue was taken-up in EtOAc (150 mL) andwashed with water (100 mL), 1 N NaOH (30 mL), and brine (30 mL), thendried (MgSO₄). The solution was filtered, and concentrated. This wasflash chromatographed on silica gel eluting with 20% acetone in hexanesto afford the protected amine (10.0 g), which was deprotected with 10 mLtrifluoroacetic acid as described herein to afford{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone39 (6.5 g), [M+H]⁺=450.

Example 4

[0205] 2-Chloro-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylEster

[0206] Step 1:

[0207]{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

[0208] To an ice-cold solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(1.0 g, 3.3 mmol) and triethylamine (0.5 ml, 3.6 mmol) under an inertatmosphere was added morpholine-4-carbonyl chloride (0.4 mL, 3.5 mmol)dropwise. The ice bath was removed and the reaction stirred at roomtemperature for 4 h. The methylene chloride was washed 2 times withwater (30 mL), dried (MgSO₄), filtered, and concentrated to afford{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanoneas an oil (1.16 g).

[0209] Step 2:

[0210]{4-[(7-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

[0211] To a −78° C. solution of{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(300 mg, 0.72 mmol) and tetrabutylammonium iodide (292 mg, 0.79 mmol) indichloromethane (20 mL) under an inert atmosphere was added borontrichloride (1 M, 2.5 mL, 2.5 mmol) dropwise. The reaction was warmed toroom temperature and stirred for 2.5 h. The reaction was quenched byslow addition of water and the organic layer separated and dried(MgSO₄). This was concentrated onto silica (1.5 g) and placed on top ofa flash column. Chromatography eluting with 30% acetone in hexanesafforded{4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(128 mg).

[0212] Step 3:

[0213] 2-Chloro-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester

[0214] To a solution of{4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solutionwas allowed to stir for 24 h at 25° C. under N₂. Concentrated in vacuo.The final product was isolated by preparative RPHPLC (YMC CombiprepODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford2-Chloro-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 40 (5.1 mg), [M+H]⁺=690.

[0215] Similarly, following the procedure described above in Example 4,but replacing 2-chlorobenzene sulfonyl chloride with the appropriatesulfonyl chlorides, the following compounds were prepared:

[0216] 2,5-dichloro-thiophene-3-sulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 41, [M+H]⁺=731;

[0217] 2-bromo-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 42, [M+H]⁺=735;

[0218] 2-cyano-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 43, [M+H]⁺=681; and

[0219] 3,5-dimethyl-isoxazole-4-sulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 44, [M+H]⁺=675. EXAMPLE 5 Composition for Oral AdministrationIngredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate  0.5%

[0220] The ingredients are mixed and dispensed into capsules containingabout 100 mg each; one capsule would approximate a total daily dosage.EXAMPLE 6 Composition for Oral Administration Ingredient % wt./wt.Active ingredient 20.0% Magnesium stearate  0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine)  1.0%

[0221] The ingredients are combined and granulated using a solvent suchas methanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine. EXAMPLE 7 Composition for Oral Administration Ingredient AmountActive compound  1.0 g Fumaric acid  0.5 g Sodium chloride  2.0 g Methylparaben  0.15 g Propyl paraben  0.05 g Granulated sugar  25.5 g Sorbitol(70% solution) 12.85 g Veegum K (Vanderbilt Co.)  1.0 g Flavoring 0.035mL Colorings  0.5 mg Distilled water q.s. to 100 mL

[0222] The ingredients are mixed to form a suspension for oraladministration. EXAMPLE 8 Parenteral Formulation (IV) Ingredient %wt./wt. Active ingredient 0.25 g Sodium Chloride qs to make isotonicWater for injection to  100 mL

[0223] The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.EXAMPLE 9 Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

[0224] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight. EXAMPLE 10 TopicalFormulation Ingredients grams Active compound 0.2-2 Span 60 2 Tween 60 2Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA(butylated hydroxy anisole) 0.01 Water q.s. 100

[0225] All of the ingredients, except water, are combined and heated toabout 60° C. with stirring. A sufficient quantity of water at about 60°C. is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. about 100 g.

Example 11 Nasal Spray Formulations

[0226] Several aqueous suspensions containing from about 0.025-0.5percent active compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 12 Radioligand Binding Studies

[0227] The inhibitory activity of compounds of this invention in vitrowas determined using a modification of the method described in Hegde, S.S. et al. 1997 Br. J. Pharmacol., 120, 1409-1418.

[0228] Cell membranes from Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (m₁-m₅) were employed. The assayswere conducted with the radioligand [³H]N-methyl scopolamine (0.4 nM,specific activity 84 Ci·mmol⁻¹) in a final volume of 0.25 mL Tris-Krebsbuffer. Non-specific binding was defined with 1 μM atropine. Assays wereperformed using scintillation proximity assay technology.Competition-displacement curves were generated using 10 concentrationsof test compounds and were analyzed by iterative curve fitting to a fourparameter logistic equation. pIC₅₀ values (-log of the IC₅₀) wereconverted to pKi values using the Cheng-Prusoff equation.

[0229] Compounds of this invention were active in this assay.Representative values for the M2 and M3 receptor are shown below. CpdStructure # Ex m2/ m3

1 1 8.57 8.83

3 1 7.38 7.31

4 1 7.58 7.29

5 1 8.50 8.23

15 1 8.37 8.17

16 1 9.01 8.80

28 1 8.30 7.94

23 1 9.24 8.56

35 2 8.74 9.05

39 3 8.66 9.02

Example 13 Oxotremorine/Pilocarpine-Induced Salivation (OIS/PIS) Modelin Anesthetized Rats.

[0230] Female Sprague-Dawley rats (Charles-River, 200-300 g) rats wereanesthetized with urethane (1.5 g/kg, sc) and were tracheotomized. Onefemoral vein was cannulated for drug administration. After a one hourstabilization period, rats were pre-treated with methoctramine (only forOIS) to antagonize M₂ receptor mediated bradycardia. Each animal wasdosed, intravenously, with a single dose of the vehicle or the referencecompound. Ten minutes later, pre-weighed cotton pads were placed in theanimals mouth following which they were dosed with vehicle oroxotremorine (0.1 mg/kg, iv)/pilocarpine (1 mg/kg, iv). Fresh cottonpads were placed at 5 minutes post-oxotremorine/pilocarpine and salivacollected for an additional 5 minutes. The cotton pads (5 and 10-minuteperiod) were then re-weighed to determine the amount of saliva secretedduring the 10-minute period.

[0231] All oxotremorine/pilocarpine treated groups were compared usingone-way analysis of variance. Pair-wise comparisons were made usingDunnett's test. The ranked data (non-parametric technique) or actuallevels of the data (parametric technique) are applied in the analysisdepending upon the results of the Bartlett's test, which testshomogeneity of variances. The vehicle/oxotremorine group andvehicle/pilocarpine was compared to the vehicle/vehicle group usingWilcox on rank-sum test. An estimate of the ID₅₀ for each compound withrespect to the 10 minute overall secretion weight for each animal wasobtained. The sigmoidal model is in the form of

Resp=min+(max−min)/(1+(dose/ID ₅₀)**N)

[0232] where ID₅₀ is the dose to achieve half the maximal response, N isthe curvature parameter and max is the max response for the doseresponse curve. The minimum response was fixed at 0 in the model.

[0233] Compounds of this invention were active in this assay.

Example 14 Inhibition of Volume-Induced Contractions in Rats

[0234] The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in rats using a modification of themethod described in Hegde, S. S. et al.1996, Proceedings of the 26thAnnual Meeting of the International Continence Society (August27th-30th), Abstract 126.

[0235] Female Sprague-Dawley rats were anesthetized with urethane andinstrumented for intravenous administration of drugs and, in some cases,measurement of arterial pressure, heart rate and intra-bladder pressure.The effect of test compounds on volume-induced bladder contractions wasdetermined in separate groups of animals. Volume-induced reflex bladdercontractions were induced by filling the bladder with saline. The testcompounds were administered intravenously in a cumulative manner at10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at theend of the study as a positive control.

[0236] Compounds of this invention were active in this assay.

Example 15 Anti-Muscarinic Activity in Anesthetized Dogs

[0237] The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in dogs using a modification of themethod described in Newgreen, D. T. et al.1996, J. Urol., 155 (Suppl.5), 1156.

[0238] Female beagles (Marshall Farms, North Rose, N.Y.) were fasted for18 hours prior to the experiment; water was allowed ad libitum. On theday of the experiment, dogs were anesthetized and maintained onpentobarbital (36 mg/kg, iv initially, then 5-10 mg/kg, iv formaintenance). Intravenous fluids were also administered to the dog forthe remainder of the experiment. The dogs were artificially ventilated,via an endotracheal tube, with an Harvard respirator (Model 613). Bothfemoral veins and one femoral artery was cannulated for drugadministration and blood pressure measurement, respectively. Bloodpressure was measured with a Gould transducer (Model P23XL) and recordedon a Gould recorder (Model 3400). A sublingual incision was made toexpose the left mandibular duct, which was then cannulated for thecollection of saliva into pre-weighed vials. The left salivary gland wasexposed via a submandibular incision. The chorda-lingual nerve wasisolated and had a bipolar electrode placed on it for stimulation. Testresponses to chorda-lingual nerve stimulation were obtained to confirmproper electrode placement.

[0239] After completion of surgery, physostigmine (180 μg/kg/h, iv) (acholinesterase inhibitor) was infused for the remainder of theexperiment. Following a one hour stabilization period, two controlchorda-lingual nerve stimulations were performed at 12 Hz, 10 V, 0.5 msduration (Grass S48). The chorda-lingual nerve was stimulated for 20seconds and 2 minutes, respectively, with a minimum of 10 minuteinterval between each set of stimulations. After two consistent controlresponses were obtained, the vehicle or the reference compound was dosedin a cumulative fashion, 3 minutes prior to each stimulation of thechorda-lingual nerve. Experiments in which consistent salivationresponses could not be obtained were not included in the analysis.Atropine (1.0 mg/kg, iv) was given as a positive control at the end ofthe study.

[0240] Mean arterial blood pressure was calculated as Diastolic arterialpressure+(Systolic arterial pressure−Diastolic arterial pressure)/3.Heart rate was derived from the pressure pulse. Saliva was collected inpre-weighed vials and weighed after each collection to determine thevolume of saliva secreted. Inhibition of salivary gland responses wereexpressed as a percent of the effect of atropine (1 mg/kg, iv). ED₅₀Estimation

[0241] For % max inhibition salivation, parameter estimation wasperformed using a nonlinear mixed model. The method was implementedusing PROC NLIN initially and PROC MIXED iteratively. This procedureassumed the following sigmoidal dose-response model:${Response} = {{Min} + \frac{{Max} - {Min}}{1 + 10^{- \frac{({x - \mu})}{\sigma}}}}$

[0242] where response=% max inhibition bladder contraction at peak,x=log₁₀ dose of treatment and the 4 parameters were: log₁₀ ED50 (μ),maximum and minimum response (Max and Min), and curvature (σ). Theminimum was assumed 0%. This method assumed compound symmetry for thecovariance structure. It was an iterative curve-fitting procedure thataccounted for the dependence between multiple measurements from the sameanimal, and estimated the desired parameters and their confidence limitsby adjusting its error calculations to account for within subjectcorrelation.

[0243] Baseline Comparisons

[0244] To compare each dose to baseline control for every variable, atwo-way ANOVA with main effects of subject and treatment was performed,followed by a pair t-test at each dose level. If the overall treatmenteffect was not significant (p-value>0.05) in ANOVA, a Bonferroniadjustment for p-values was used for the p-value of pair t-test at eachdose.

[0245] Compounds of this invention were active in this assay.

Example 16 In Vivo Antimuscarinic Activity in Bronchoconstriction Assays

[0246] Antagonist activity is assessed against methacholine-inducedbronchoconstriction and bradycardia in the anesthetized rat modelfollowing a procedure similar to that described by Hirose et al, 2001,J. Pharm. Exp. Ther., Vol 297, 790-797. Compounds are givenintravenously, orally or by intratracheal instillation prior tochallenge with intravenous methacholine. Lung resistance and dynamiccompliance are used as indices of bronchoconstriction.

[0247] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. This invention relates to compounds comprisingFormula I:

wherein: R¹ is (C₁₋₆)alkyl; R² is halogen or —OR′; R³ is hydrogen or—OR′; R′ is hydrogen, (C₁₋₆)alkyl, or SO₂R′; R″ is (C₁₋₆)alkyl,haloalkyl, aryl or heteroaryl, wherein said aryl or heteroaryl groupsare optionally substituted with a group selected from (C₁₋₆)alkyl, halo,haloalkyl, cyano, nitro, alkylsulfonyl, and alkylsulfonylamino; R⁴ is(i) (C₁₋₆)alkyl, (ii) aryl, heterocyclyl, or heteroaryl, wherein saidaryl, heterocyclyl or heteroaryl groups are optionally substituted witha group selected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano,amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl,urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl, or (iii) —NR⁵R⁶; and R⁵ andR⁶ are independently of each other hydrogen, (C₁₋₆)alkyl, aryl orheterocyclyl; wherein said aryl or heterocyclyl groups are optionallysubstituted with (C₁₋₆)alkyl, halo, haloalkyl, cyano, (C₁₋₆)alkoxy, andalkylsulfonyl; or an individual isomer, a racemic or non-racemic mixtureof isomers, or an acceptable salt or solvate thereof.
 2. The compound ofclaim 1, wherein R² is (C₁₋₆)alkoxy and R³ is hydrogen.
 3. The compoundof claim 1, wherein R² is (C₁₋₆)alkoxy and R³ is (C₁₋₆)alkoxy.
 4. Thecompound of claim 1, wherein R² is —OSO₂R″ and R³ is hydrogen.
 5. Thecompound of claim 1, wherein R² is hydroxy and R³ is hydrogen.
 6. Thecompound of claim 1, wherein R² is halogen and R³ is hydrogen.
 7. Thecompound of claim 1 wherein R⁴ is (C₁₋₆)alkyl.
 8. The compound of claim7, wherein R¹ is ethyl or propyl.
 9. The compound of claim 8, wherein R²is —OR′, and R³ is —OR′ or hydrogen.
 10. The compound of claim 1,wherein R⁴ is an aryl group.
 11. The compound of claim 10, wherein R⁴ isphenyl optionally substituted with a group selected from (C₁₋₆)alkyl,halo, haloalkyl, (C₁₋₆)alkoxy, cyano, amino, mono- or di alkylamino,nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino,alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl andheteroaryl.
 12. The compound of claim 10, wherein R¹ is ethyl or propyl.13. The compound of claim 11, wherein R¹ is ethyl or propyl.
 14. Thecompound of claim 13, wherein R² is —OR′, and R³ is —OR′ or hydrogen.15. The compound of claim 1, wherein R⁴ is a heteroaryl group.
 16. Thecompound of claim 15, wherein R⁴ is selected from furanyl, thiophenyl,isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionallysubstituted with one or two (C₁₋₆) alkyl.
 17. The compound of claim 15,wherein R¹ is ethyl or propyl.
 18. The compound of claim 16, wherein R¹is ethyl or propyl.
 19. The compound of claim 18, wherein R² is —OR′,and R³ is —OR′ or hydrogen.
 20. The compound of claim 1, wherein R⁴ is aheterocyclyl group.
 21. The compound of claim 20, wherein R⁴ ispiperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or diazepanyl, alloptionally substituted with one or two (C₁₋₆)alkyl or alkylcarbonylgroups.
 22. The compound of claim 20, wherein R⁴ is piperidin-4-yl,optionally substituted with one or two (C₁₋₆)alkyl groups oralkylcarbonyl groups.
 23. The compound of claim 20, wherein R⁴ ispiperidin-1-yl, optionally substituted with one or two (C₁₋₆)alkylgroups.
 24. The compound of claim 20, wherein R⁴ is pyrrolidin-1-yl,optionally substituted with one or two (C₁₋₆)alkyl groups.
 25. Thecompound of claim 20, wherein R⁴ is [1,4]-diazepany-1-yl, optionallysubstituted with one or two (C₁₋₆)alkyl groups.
 26. The compound ofclaim 20, wherein R⁴ is piperazin-1-yl, optionally substituted with oneor two (C₁₋₆)alkyl groups.
 27. The compound of claim 20, wherein R⁴ ismorpholinyl, optionally substituted with one or two (C₁₋₆)alkyl groups.28. The compound of claim 20, wherein R¹ is ethyl or propyl.
 29. Thecompound of claim 21, wherein R¹ is ethyl or propyl.
 30. The compound ofclaim 29, wherein R² is —OR′, and R³ is —OR′ or hydrogen.
 31. Thecompound of claim 1, wherein R⁴ is —NR⁵R⁶.
 32. The compound of claim 31,wherein R⁵ is (C₁₋₆)alkyl, and R⁶ is hydrogen or (C₁₋₆)alkyl.
 33. Thecompound of claim 31, wherein R¹ is ethyl or propyl.
 34. The compound ofclaim 33, wherein R² is —OR′, and R³ is —OR′ or hydrogen.
 35. Thecompound of claim 1, comprising:{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone;{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone;{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone;and{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone.36. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in admixture with an acceptable carrier.37. The pharmaceutical composition of claim 36, wherein the compound issuitable for administration to a subject having a disease state which isalleviated by treatment with a M2/M3 muscarinic receptor antagonist. 38.A method of treating a subject which comprises administering to thesubject with a disease treatable with a M2/M3 muscarinic antagonist atherapeutically effective amount of one or more compounds of claim 1.39. The method of claim 38, wherein the disease state is associated withsmooth muscle disorders comprising diseases of the genitourinary orgastrointestinal tract, or of respiratory states.
 40. The method ofclaim 39, wherein the disease state is associated with the genitourinarytract.
 41. The method of claim 40, wherein the disease state comprisesoveractive bladder, detrusor hyperactivity, urgency, frequency, reducedbladder capacity, incontinence episodes, changes in bladder capacity,micturition threshold, unstable bladder contractions, sphinctericspasticity, outlet obstruction, outlet insufficiency, pelvichypersensitivity, idiopathy conditions, or detursor instability.
 42. Themethod of treatment of claim 39, wherein the disease state comprisesrespiratory states.
 43. The method of treatment of claim 42, wherein thedisease state comprises respiratory states from allergies or asthma. 44.The method of treatment of claim 39, wherein the disease state comprisesgastrointestinal tract disorders.
 45. A process for preparing a compoundas claimed in claim 1 which process comprises reacting a compound havinga general formula d:

wherein R¹, R² and R³ are as described in claim 1, with a compound ofgeneral Formula R⁴C(O)L, wherein L is a leaving group and R⁴ is asdescribed in claim 1, to prepare a compound of Formula I

wherein R¹, R², R³ and R⁴ are as described in claim 1.